DNA strand breaks, neurodegeneration and aging in the brain

Abstract

Defective responses to DNA single-or double-strand breaks can result in neurological disease, underscoring the critical importance of DNA repair for neural homeostasis. Human DNA repairdeficient syndromes are generally congenital, in which brain pathology reflects the consequences of developmentally incurred DNA damage. Although, it is unclear to what degree DNA strandbreak repair defects in mature neural cells contributes to disease pathology. However, DNA single-strand breaks are a relatively common lesion which if not repaired can impact cells via interference with transcription. Thus, this lesion, and probably to a lesser extent DNA double strand breaks, may be particularly relevant to aging in the neural cell population. In this review we will examine the consequences of defective DNA strand break repair towards homeostasis in the brain. Further, we also consider the utility of mouse models as reagents to understand the connection between DNA strand breaks and aging in the brain.

Wolf–Hirschhorn syndrome candidate 1 is involved in the cellular response to DNA damage

“…A-T, which is caused by mutations in ATM, is characterized by progressive neurologic impairment, cerebellar ataxia, variable immunodeficiency, and a predisposition to malignancy (10). Other examples of DDR syndromes that affect the development and homeostasis of the nervous and immune system include the Nijmegen breakage syndrome and the ataxiatelangiectasia-like disorder, which are due to mutations in the DDR factors NBS1 and MRE11, respectively (11,12). Mutations in ATR, and other components of the ATR pathway, have been identified in Seckel syndrome patients with microcephaly, facial dysphormism, and growth defects (12).…”

Neurodegeneration-associated instability of ribosomal DNA.

“…The age related accumulation of DNA damage, and the subsequent genomic instability which follows, has been proposed as a mechanism for proliferative senescence, cancer, and neurodegeneration, all of which are associated with aging or aging related disorders [1][2][3]. DNA damage is well documented in neurodegeneration and in some cases it may be sufficient to cause disease [1,4].…”

“…DNA damage is well documented in neurodegeneration and in some cases it may be sufficient to cause disease [1,4]. Moreover, significant increases in oxidative DNA damage are known to occur in Alzheimer's disease, Parkinson's disease, and Dementia with Lewy Bodies [5,6].…”

The regulation of RNA Polymerase I-mediated transcription in forebrain neurons.

“…Genetic defects of several DNA repair pathways, including those for single-or double DNA strand breaks (SSBs or DSBs, respectively) as well as large chemical modifications of DNA bases that are also known as 'bulky' DNA ad ducts (Brooks, 2008;Caldecott, 2008;Katyal and McKinnon, 2008) provide a strong argument for a causative role of DNA damage in common neurodegenerative disorders. For instance, deficiencies of the DSB repair kinase ataxia telangiectasia-mutated protein kinase (ATM) trigger delayed neurodegeneration, presumably by blocking the developmental apoptosis of newly generated neurons harboring chromosomal abnormalities (Katyal and McKinnon, 2008).…”

“…For instance, deficiencies of the DSB repair kinase ataxia telangiectasia-mutated protein kinase (ATM) trigger delayed neurodegeneration, presumably by blocking the developmental apoptosis of newly generated neurons harboring chromosomal abnormalities (Katyal and McKinnon, 2008). In contrast, the SSBlbulky adducts repair deficits may induce neurodegeneration by the progressive and age-dependent accumulation ofunrepaired DNA damage that reduces neuronal transcription (Brooks, 2008;Caldecott, 2008;Katyal and McKinnon, 2008).…”